Phospholipids can be shown to undergo marked shifts in composition during the process of myeloid differentiation. It is currently unknown if this represents an epiphenomenon or is of crucial mechanistic importance. The promyelocytic leukemia line, HL-60, is being used to study this question. We have utilized a range of predicted lipid intermediates and antimetabolites to dissect the contribution of lipids to the complex set of biochemical changes that occur with differentiation, particularly the role of phospholipid methylation and arachidonic acid release.